Project 2 will examine the role of infiltrating immune cells in the renal medulla in the pathogenesis of salt-sensitive hypertension and renal injury. Preliminary and published data indicate that salt-sensitive hypertension in both a genetic and an experimental rat model of disease is associated with extensive renal injury, infiltration of immune cells into the kidney, and increased intrarenal angiotensin II (ANGII) levels. Interestingly, pharmacological blockade of the immune system or of ANGII receptors attenuates the development of hypertension and kidney damage in these disease models. Furthermore, administration of immunosuppressive drugs directly into the renal medullary interstitial space decreases the severity of hypertension, indicating that immune cell infiltration in the renal medulla is important in the pathophysiology of salt-sensitive hypertension. Using these novel data as a rationale and a unique integrative experimental approach, we will test the hypothesis that the infiltration of immune cells into the renal medulla following an initial increase in arterial blood pressure after exposure to a high salt diet (4% NaCI) mediates the further development of hypertension and kidney disease in Dahl Salt-Sensitive (SS) rats and in the salt-sensitive hypertension that occurs following apparent recovery from renal ischemia-reperfusion injury in normal rats. We further propose that the immune cells act by releasing ANGII which serves to increase the severity of hypertension and renal damage. This novel hypothesis will be addressed in three Specific Aims. Aim 1 will determine the importance of immune cell infiltration into the renal medullary interstitial space in the secondary phase of genetic and experimental forms of salt-sensitive hypertension. Aim 2 will determine the ability of infiltrating immune cells to synthesize and release ANGII into the kidney in experimental and genetic forms of salt-sensitive hypertension. Aim 3 will determine the role of infiltrating immune cells in the kidney on renal hemodynamics and the renal handling of sodium and water in experimental and genetic forms of salt-sensitive hypertension.